The present invention relates to a process for preparing 6-O-substituted erythromycin derivatives and 6-O-substituted erythromycin ketolides thereof. Specifically, the invention relates to a palladium-catalyzed process for preparing 6-O-substituted erythromycin derivatives from erythromycins using alkylating agents in presence of a phosphine and their subsequent conversion into 6-O-substituted erythromycin ketolides.
6-O-Methylerythromycin A (clarithromycin) is a potent macrolide antibiotic disclosed in U.S. Pat. No. 4,331,803.
The process for making clarithromycin, in general, can be thought of as a four-step procedure beginning with erythromycin A as the starting material:
Step 1: optionally convert the 9-oxo group to an oxime;
Step 2: protect the 2xe2x80x2 and 4xe2x80x3 hydroxyl groups;
Step 3: methylate the 6-hydroxyl group; and
Step 4: deprotect at the 2xe2x80x2, 4xe2x80x3 and 9-positions.
A variety of means for preparing 6-O-methylerythromycin A have been described in the literature. 6-O-Methylerythromycin A can be prepared by methylating a 2xe2x80x2-O-3xe2x80x2-N-dibenzyloxycarbonyl-des-N-methyl derivative of erythromycin A (U.S. Pat. No. 4,331,803). 6-O-Methylerythromycin A can also be made from 9-oxime erythromycin A derivatives (See, e.g., U.S. Pat. Nos. 5,274,085; 4,680,386; 4,668,776; 4,670,549 and 4,672,109, 4,990,602 and European Patent Application 0260938 A2). Several commonly-owned U.S. Pat. Nos. 5,872,229; 5,719,272; 5,852,180; 5,864,023; 5,808,017; 5,837,829 and 5,929,219 disclose the use of alternate protecting groups for the oxime hydroxyl, and the 2xe2x80x2- and 4xe2x80x3-hydroxyls in the process of making the 6-O-methyl erythromycin derivatives.
Since the discovery of clarithromycin, new macrolide antibiotic compounds have been discovered. New classes of particularly effective macrolide antibiotics are disclosed in U.S. Pat. No. 5,866,549. The 6-O-position of the macrolide core can be substituted with a C2-C6 alkenyl group. Such compounds generally have been prepared by the processes described for the preparation of 6-O-methylerythromycin A. However, the substitution at the 6-O-position with substituents other than the methyl group is not easy to accomplish and is accompanied by side reactions, by-products and low yields.
Therefore, there is considerable effort directed towards discovering more efficient and cleaner methods of introducing substituents other than the methyl in the 6-position of the erythromycin derivatives.
Palladium-catalyzed allylation of alcohol hydroxyl groups is known in the literature. See for example, Lakhmiri et al., xe2x80x9cSynthesis De O-glycosides D""Alcenylesxe2x80x9d, J. Carbohydrate Chemistry, 12(2), 223, (1993); Lakhmiri et al., Tetrahedron Letters, 30(35), No. 35, pp 4673-4676, (1989); and Lakhmiri et al., xe2x80x9cAn Improved Synthesis of Allyl Ethers of Carbohydratesxe2x80x9d, Synthetic Communications, 20 (10), 1551-1554 (1990). Palladium-catalyzed allylation of phenol derivatives using allyl t-butyl carbonate is disclosed in Goux C. et al., Synlett., 725 (1990). However, there are no known reports of palladium-catalyzed substitution, derivatization or selective allylation of hydroxyl groups of erythromycin derivatives.
In one aspect, therefore, the present invention relates to a process for preparing 6-O-substituted erythromycin derivatives comprising reacting an erythromycin derivative with an alkylating agent having the formula: 
wherein
R is independently selected from the group consisting of:
hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl at each occurrence;
R1 is an alkyl group of one to ten carbon atoms, and
X is O or NRxe2x80x2, wherein Rxe2x80x2 is alkyl or aryl, or R1 and Rxe2x80x2 taken together form an aromatic or non-aromatic ring;
in the presence of a palladium catalyst and a phosphine.
The erythromycin derivative used in the process of the invention is represented by formula (1) below: 
wherein:
Rp is independently a hydrogen or a hydroxyl-protecting group at each ocurrence except that Rp may not simultaneously be hydrogen at both positions;
V is selected from the group consisting of:
a) O
b) an oxime having the formula Nxe2x80x94Oxe2x80x94R2; wherein
R2 is selected from the group consisting of:
hydrogen,
a loweralkenyl group,
an aryl(loweralkyl) group, and
a substituted aryl(loweralkyl) group;
c) an oxime having the formula 
wherein
R3 is selected from the group consisting of:
alkyl,
alkylaryl,
aryl, and
substituted aryl;
d) an oxime having the formula 
wherein
R4 is selected from the group consisting of:
a loweralkyl group,
a cycloalkyl group,
a phenyl group, and
an aryl(loweralkyl) group;
or R and R5 or R4 and R6 and the atoms to which they are attached are taken together form a 5- to 7-membered ring containing one oxygen atom; and
R5 and R6 are independently selected from the group consisting of:
a hydrogen atom,
a loweralkyl group,
a phenyl group,
an aryl(loweralkyl) group;
or any pair of substituents selected from (R4 and R5), (R4 and R6) or (R5 and R6) and the atoms to which they are attached are taken together to form a 5- to 7-membered ring optionally containing one oxygen atom; provided that only one pair of substituents (R4 and R5), (R4 and R6) or (R5 and R6) may be taken together with the atoms to which they are attached to form a ring as defined above;
e) an oxime having the formula: 
wherein R7, R8, and R9 are independently selected at each occurrence from hydrogen, loweralkyl, aryl-substituted alkyl, aryl, cycloalkyl, and loweralkenyl;
f) 
wherein R10 and R11 are independently selected at each occurrence from hydrogen, alkyl, or nitrogen-protecting group, or R10 and R11 taken together form a 5- to 7-membered cycloalkyl ring; and
g) 
wherein R12 and R13 are independently selected at each occurrence from hydrogen, alkyl or a nitrogen-protecting group; or R12 and R13 taken together form a 5- to 7-membered cycloalkyl ring; and
Z is hydroxyl or a protected hydroxyl group.
The 6-O-substituted erythromycin derivative is represented by formula (II) 
wherein Ra is represented by the formula: 
and wherein R, Rp, V and Z are as defined above.
The compounds of formula (II) may be optionally deprotected and deoximated to obtain compounds of formula (III) 
wherein Rp, Ra and Z are as defined above.
The compounds of formulas (I), (II) and (III) are useful intermediates in the synthesis of macrolide antibiotics as described in the U.S. Pat. No. 5,866,549, issued Feb. 2, 1999, represented by formula (IV) 
Therefore, in another aspect, the process of invention further comprises the steps of:
(a) reacting the compound of formula (III) 
with 1,1xe2x80x2-carbonyldiimidazole in the presence of an amine base or an amine base catalyst followed by a reaction with ammonia or ammonium hydroxide optionally carried out in the presence of a strong base to give a compound having the formula: 
(b) removing the cladinose moiety from the compound obtained in step (a) by hydrolysis with acid to give a compound having the formula: 
(c) oxidizing the 3-hydroxyl group, and optionally deprotecting and isolating the desired compound.
In yet another aspect, the present invention relates to the process for preparing a compound of formula (IV) by removing the cladinose moiety of a compound of formula (Ixe2x80x2) with acid; protecting the 2xe2x80x2- and optionally the 3-hydroxyl functionalities; alkylating the compound obtained therefrom with an alkylating agent; deoximating; preparing an 11,12-cyclic carbamate; deprotecting the 3-hydroxyl, if protected; oxidizing the 3-hydroxyl group; and optionally deprotecting the 2xe2x80x2-hydroxyl to afford a compound of formula (IV). The process of the invention is an efficient process and provides higher yields of the desired compounds compared with known alkylation processes.
A number of terms are used herein to designate particular elements of the present invention. When so used, the following meanings are intended:
The term xe2x80x9cerythromycin derivativexe2x80x9d refers to erythromycins having a 9-keto group or wherein the 9-keto group is converted into an oxime having no substituents or specified substituents in place of the oxime hydroxyl hydrogen and optionally having conventional protecting groups in place of the hydrogen of the 2xe2x80x2 and 4xe2x80x3 hydroxyl groups.
The term xe2x80x9cerythromycin 9-oxime derivativexe2x80x9d as used herein refers to erythromycins wherein the 9-keto group is converted into an oxime as described above.
The term xe2x80x9c6-O-substituted erythromycin derivativesxe2x80x9d as used herein refers to erythromycin 9-oxime derivatives or erythromycins having the hydrogen of the 6-hydroxyl group substituted with various substituents.
The term xe2x80x9chydroxyl-protecting groupxe2x80x9d is well-known in the art and refers to substituents on functional hydroxyl groups of compounds undergoing chemical transformation which prevent undesired reactions and degradations during a synthesis (see, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York (1999)). Examples of hydroxyl-protecting groups include, but are not limited to, benzoyl, benzyloxycarbonyl, acetyl, or a substituted silyl group of formula SiR7R8R9, wherein R7, R8 and R9 are the same or different and each is a hydrogen atom, a loweralkyl group, an aryl-substituted alkyl group in which the alkyl moiety has 1 to 3 carbon atoms, an aryl group, a cycloalkyl group having 5 to 7 carbon atoms, or a loweralkenyl group having 2 to 5 carbon atoms and wherein at least one of R7, R8 and R9 is not a hydrogen atom; and the like.
The term xe2x80x9calkylxe2x80x9d or xe2x80x9cloweralkylxe2x80x9d refers to an alkyl radical containing one to six carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and neopentyl.
The term xe2x80x9cloweralkoxyxe2x80x9d refers to a loweralkyl group as previously defined attached to a parent molecular moiety by an ether linkage.
The term xe2x80x9cloweralkoxy(methyl)xe2x80x9d refers to an alkoxy group as described above attached to a parent molecular moiety via a methylene group (xe2x80x94CH2xe2x80x94).
The term xe2x80x9cprotected hydroxylxe2x80x9d refers to a hydroxyl group protected with a hydroxyl protecting group, as defined above.
The term xe2x80x9cpolar aprotic solventxe2x80x9d refers to polar organic solvents lacking an easily removed proton, including, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-dichloroethane, acetonitrile or ethyl acetate, and the like or a mixture thereof.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, benzyloxycarbonyl, cyano, hydroxyl, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, carboxamide, and protected hydroxyl. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, refers to a mono- or bicyclic fused aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
The term xe2x80x9csubstituted arylxe2x80x9d as used herein refers to an aryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group. Also, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9csubstituted heteroarylxe2x80x9d as used herein refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein refers to those carboxylate salts, esters, and prodrugs of the compound of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
Pharmaceutically acceptable salts are well known in the art and refer to the relatively non-toxic, inorganic and organic acid addition salts of the compound of the present invention. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) which is incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As used herein, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d represents an aggregate that comprises one or more molecules of the solute, such as a compound of the invention, with one or more molecules of solvent.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
A process of the invention involves preparing a compound of formula (IV) by reacting a compound of formula (I) with a suitable alkylating agent to obtain a compound of formula (II), and carrying out the subsequent transformations as previously described in steps (a)-(c) above. The process of the invention is illustrated in Scheme 1 below. 
In accordance with Scheme 1, the 9-keto group of erythromycins of formula 1 can be initially converted into an oxime by methods described in U.S. Pat. No. 4,990,602, followed by the protection of the 2xe2x80x2- and optionally protecting the 4xe2x80x3-hydroxyl groups of the erythromycin derivatives to obtain erythromycin 9-oxime of formula (1).
The preparation of protected erythromycins is also described in the U.S. Pat. Nos. 4,990,602; 4,331,803; 4,680,386; and 4,670,549 which are incorporated herein by reference. Also incorporated by reference is European Patent Application EP 260,938.
The C-9-carbonyl group of erythromycin can be protected as an oxime represented by V having the formula Nxe2x80x94Oxe2x80x94R2, 
Nxe2x80x94Oxe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94R4, or 
wherein R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above. Preferred oximes are those wherein V is O-(1-isopropoxycyclohexylketal) oxime, and O-benzoyloxime.
Silyl ethers are also particularly useful for protecting the 2xe2x80x2- and the 4xe2x80x3-hydroxyl groups of erythromycin derivatives. The use of silyl ether groups to protect a 9-oxime moiety and the 2xe2x80x2- and 4xe2x80x3-hydroxyl groups is described in U.S. Pat. No. 5,892,008.
The 9-carbonyl group of the erythromycins may also be protected by converting it into erythromycin 9-hydrazone as described in U.S. application Ser. No. 08/927,057 filed Sep. 10, 1997, which issued as U.S. Pat. No. 5,929,219 on Jul. 27, 1999.
The methods of preparing hydrazones are described in Sigal et al., J. Am. Chem. Soc., 78, 388-395, (1956). As for example, the 9-hydrazone is prepared by heating erythromycin at reflux in an alcoholic solvent such as methanol, ethanol or isopropanol in the presence of hydrazine until no starting material remains. The reaction typically lasts from about 12 to 36 hours. The solvent is then removed and the crude solid so obtained is used without further purification.
The amino nitrogen of the 9-hydrazone erythromycin derivative may optionally be protected by the nitrogen protecting groups by the methods described in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York, Chapter 7, (1999); and P. J. Kocienski, Protective Groups, Thieme, Chapter 6, (1994); and the references cited therein.
As for example, the amino nitrogen of the 9-hydrazone is protected by treating erythromycin 9-hydrazone with 1-2 equivalents of a silylating agent such as triisopropylsilyl triflate in the presence of an organic base such as triethylamine in an aprotic solvent. Preferably, the reaction is carried out in the presence of triethylamine in dichloroethane. The reaction results in the formation of 9-(N-triisopropylsilyl) hydrazone erythromycin derivative which can be protected at the 2xe2x80x2- and optionally at the 4xe2x80x3-positions.
The erythromycin 9-hydrazone derivative may also be converted into an azine by the methods described in, for example, U.S. Pat. No. 3,780,020 and German Patent 1,966,310. As for example, the azine derivative is prepared by treating the hydrazone with an appropriate ketone, aldehyde or an acetal thereof or an orthoformate with or without a co-solvent and either with or without an added dehydrating agent such as molecular sieves. The reaction is carried out at a temperature between room temperature and the boiling point of the ketone, aldehyde, or the co-solvent. The reaction is carried out for about one hour to about 24 hours. The azine nitrogen may be further protected by treating the 9-azine erythromycin derivative with an appropriate ketal in the presence of catalytic quantity of acid such as formic or acetic acid. The reaction mixture is stirred at ambient temperature overnight for 6 to 18 hours. The mixture is then adjusted with base to pH 8-13 and the product extracted into an appropriate solvent.
The 2xe2x80x2- and 4xe2x80x3-hydroxyl groups are protected by reaction with a suitable hydroxyl protecting reagent in an aprotic solvent. Typical hydroxyl-protecting reagents include, but are not limited to, acetylating agents, silylating agents, acid anhydrides, and the like. Examples of hydroxyl protecting reagents are, for example, acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, and trialkylsilyl chlorides.
Examples of aprotic solvents are dichloromethane, chloroform, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents do not adversely affect the reaction. Preferably, the solvent is selected from dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran, N-methyl pyrrolidinone or a mixture thereof. A more thorough discussion of solvents and conditions for protecting the hydroxy group can be found in T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Son, Inc., 1999, which is incorporated by reference.
Protection of 2xe2x80x2- and 4xe2x80x3-hydroxyl groups of compound 1 may be accomplished sequentially or simultaneously to provide compound (I), wherein Rp can be, for example, acetyl, benzoyl, trimethylsilyl, and the like. Preferred protecting groups include acetyl, benzoyl, and trimethylsilyl. A particularly preferred group for protecting the hydroxyl and the oxime moieties is the benzoate protecting group, wherein Rp is benzoyl.
Benzoylation of the hydroxyl group is typically accomplished by treating the erythromycin 9-oxime derivative with a benzoylating reagent, for example a benzoyl halide and benzoyl anhydride. A preferred benzoyl halide is benzoyl chloride. Typically, the reaction is accomplished with a benzoic anhydride, which affords the protected erythromycin 9-oxime derivative. Benzoic anhydride is a relatively expensive reagent for the protection of the erythromycin 9-oxime compound.
Alternatively, the erythromycin 9-oxime derivative can be treated with sodium benzoate and benzoyl chloride to afford the protected erythromycin 9-oxime compound. The reagent combination is a more cost-effective alternative to using benzoic anhydride. By generating benzoic anhydride in situ, the reaction allows for the efficient, effective hydroxylation of the 2xe2x80x2- and the 4xe2x80x3-protecting groups and the 9-oxime by using cheaper and more readily available starting materials. Generally, from about 3 to about 4.5 molar equivalents of benzoyl chloride and sodium benzoate are used for each equivalent of erythromycin A 9-oxime. The preferred reaction is carried out using about a 1:1 molar ratio of benzoyl chloride and sodium benzoate. Preferably, the reaction is carried out in tetrahydrofuran as the solvent, optionally in the presence of a base, for example triethylamine or imidazole.
Typically, the erythromycin derivative is isolated after oximation and before treatment with the suitable protecting group. However, the conversion of the erythromycin A with hydroxylamine and formic acid in a methanolic solvent affords an erythromycin A 9-oxime derivative that can be directly converted to the protected erythromycin A 9-oxime derivative without isolation. The preferred amount of hydroxylamine is from about 7 to about 10 molar equivalents relative to the erythromycin A. From about 2 to about 5 moles of formic acid are used for each mole of the erythromycin A starting material.
For the unisolated erythromycin A 9-oxime intermediate, it is preferred that the benzoylation is carried out with benzoic anhydride reagent, optionally in the presence of base. The reaction can be carried out in tetrahydrofuran optionally in a mixture with isopropyl acetate to afford the protected erythromycin A 9-oxime intermediate compound.
The erythromycin derivative of formula (I) is then reacted with an alkylating agent of the formula: 
wherein R, R1, and X are as defined above,
in the presence of a palladium catalyst and a phosphine promoter to obtain the compound represented by formula (II) 
wherein Ra, Rp, V and Z are as defined above.
Most palladium(0) catalysts are expected to work in this process. Some palladium(II) catalysts, such as palladium(II) acetate, which is converted into a palladium(0) species in-situ by the actions of a phosphine, will work as well. See, for example, Beller et. al. Angew Chem. Int. Ed. Engl., 1995, 34 (17), 1848. The palladium catalyst can be selected from, but is not limited to, the group consisting of palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium, (tetradibenzylideneacetone)dipalladium and the like. Palladium on carbon and palladium(II) halide catalysts are less preferred than other palladium catalysts for this process.
The ratio of palladium catalyst to the phosphine generally ranges from about 2:1 to about 1:8.
Suitable phosphines include, but are not limited to, triphenylphosphine, bis(diphenylphosphine)methane, bis(diphenylphosphine)ethane, bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, bis(diphenylphosphine)pentane, and tri(o-tolyl)phosphine, and the like.
The reaction is carried out in an aprotic solvent, preferably at elevated temperature, preferably at or above 50 xc2x0 C. The aprotic solvent includes, but is not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane, methyl-t-butyl ether (MTBE), heptane, acetonitrile, isopropyl acetate and ethyl acetate. The most preferred solvents are tetrahydrofuran or toluene.
The alkylating agents useful in the process of the invention are carbonates and carbamates of allylic hydrocarbons, for example allyl carbonates and allyl carbamates. Generally, the alkylating agents useful for the reaction generally have the formula previously described wherein R1 is from about 1 to 10 carbon atoms. The preferred alkylating agents are those wherein R1 is t-butyl group, isopropyl or N,N-diisopropyl, for example, t-butyl carbonate, isopropyl carbonate or N,N-diisopropyl carbamate compounds. Alkylating agents can include, for example, allyl iso-propyl carbonate, allyl t-butyl carbonate, allyl N,N-diisopropyl carbamate, 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate, and 1-(3-quinolyl)-2-propene-1-ol t-butyl carbonate. The alkylating reagents are obtained by reaction of an alcohol with a wide variety of compounds for incorporating the carbonate or carbamate moiety. The compounds include, but are not limited to, t-butyl chloroformate, 2-(t-butoxycarbonyl-oxyimino)-2-phenyl-acetonitrile, N-t-butoxycarbonyloxy succinimide, di-t-butyl dicarbonate, and 1-(t-butoxy-carbonyl)imidazole and the reaction is carried out in the presence of an organic or an inorganic base. The temperature of the reaction varies from about xe2x88x9230xc2x0 C. to about 30xc2x0 C. Preferably, the alkylating reagent is di-t-butyl dicarbonate.
An alternate method of converting the alcohol into the carbonate or carbamate involves treating the alcohol with phosgene or triphosgene to prepare the chloroformate derivative of the alcohol. The chloroformate derivative is then converted into the carbonate or carbamate by the methods described in Cotarca, L., Delogu, P., Nardelli, A., Sunijic, V. Synthesis, 1996, 553. The reaction can be carried out in a variety of organic solvents such as dichloromethane, toluene, diethyl ether, ethyl acetate and chloroform in the presence of a base. Examples of bases include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, dimethylaminopyridine, pyridine, triethylamine and the like. A wide variety of phase transfer reagents can be used, including tetrabutylammonium halide and the like. The temperature conditions can vary anywhere from 0xc2x0 C. to about 60xc2x0 C. The reaction typically takes about 3 to 5 hours to run to completion.
One example of a method for preparing the alkylating agent is described in the commonly owned, U.S. Application Serial No. 60/141,042, filed on Jun. 24, 1999, and is illustrated in Scheme 2 below. 
According to Scheme 2, commercially available 3-bromoquinoline is reacted with propargyl alcohol in the presence of an organic base, palladium catalyst and a copper halide or a phase transfer agent, such as tetrabutylammonium bromide. The reaction is carried out at a temperature from about 40xc2x0 C. to about 90xc2x0 C.
The 3-(3-quinolyl)-2-propyn-1-ol (i) thus obtained is then reduced by one of the two methods to produce 3-(3-quinolyl)-2-propen-1-ol. The reduction may be accomplished either by catalytic hydrogenation using hydrogen gas and a palladium or a platinum catalyst at room temperature to produce the cis-isomer or using a metal hydride type reagent, for example aluminum hydride reagents. Reaction with lithium aluminum hydride (LAH) and sodium bis(2-methoxyethoxy)aluminum hydride in toluene (Red-Al) between xe2x88x9220xc2x0 C. to about 25xc2x0 C. produce the trans-isomer. Certain additives are suitable for the catalytic hydrogenation reaction and can afford the cis-isomer in good yield. One suitable additive is 3,6-dithia-1,8-octanediol, however, various other additives can be used in the hydrogenation.
The 3-(3-quinolyl)-2-propen-1-ol obtained above is then converted into a carbonate by reaction with a wide variety of reagents or into a carbamate by known literature methods, as shown below, 
wherein X and R1 are as previously defined. For example, the allylic alcohol, 3-(3-quinolyl)-2-propen-1-ol can be reacted with di-t-butyl dicarbonate at 0xc2x0 C. in the presence of a hydroxylic base, such as sodium hydroxide to give the corresponding carbonate. See, Houlihan et al., Can. J. Chem. 1985, 153.
Compounds of formula (II) are then converted into the compounds of formula (III) by optional deprotection and deoximation. The deprotection of the oxime hydroxyl group is carried out under neutral, acidic or basic conditions depending upon the nature of the protecting group. Conditions for deprotecting a protected oxime of the formula Nxe2x80x94Oxe2x80x94C(O)xe2x80x94R3 include, but are not limited to, treatment with an alcoholic solvent at room temperature or reflux or treatment with a primary amine, such as butylamine. Alcoholic solvents preferred for the deprotection are methanol and ethanol. The protected oxime of formula Nxe2x80x94Oxe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94R4 can be converted with aqueous acid in acetonitrile, for example aqueous acetic acid, hydrochloric acid or sulfuric acid. A more thorough discussion of the procedures, reagents and conditions for removing protecting groups is described in literature, for example, by T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Son, Inc., 1999, which is incorporated herein by reference.
Deoximation of the 9-oxime can be carried out according to the methods described in the literature, for example by Greene (op. cit.) and others. Examples of deoximating agents are inorganic nitrite or sulfur oxide compounds such as sodium nitrite, sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrogensulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, potassium metabisulfite and the like. Examples of the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol, or a mixture of one or more of the mentioned solvents and the like. Some aprotic solvents can be used in the reaction either alone, or in an aqueous solution, for example tetrahydrofuran.
The deoximation reaction is more conveniently carried out in the presence of an acid such as formic acid, acetic acid, citric acid, oxalic acid, tartaric acid, and trifluoroacetic acid. The amount of acid used is from about 1 to about 10 equivalents of the amount of compound of formula (11) used. In a preferred reaction, the deoximation is carried out using sodium sulfite in the presence of an organic acid, such as tartaric acid. The preferred reaction is carried out in tetrahydrofuran and water to afford a corresponding 9-keto erythromycin derivative.
Compound (III) is then reacted with carbonyldiimidazole in the presence of a strong base to convert the 11,12-diol intermediate directly into a 12-acylimidazolide intermediate. Examples of a suitable base include an alkali metal hydride, an amine base, or an amine base catalyst. The preferred bases are sodium hexamethyldisilazide and 1,8-diaza-bicyclo[5.4.0]-undec-7-ene (DBU). Treatment with sodium hexamethyldisilazide and DBU can be followed by treatment with ammonia or ammonium hydroxide to afford the cyclic carbamate. The alkali metal can be sodium, potassium, or lithium and the aprotic solvent can be one of those defined above.
The conversion reaction can be carried out in two steps. The first step involves the reaction of compound (III) with base in the presence of carbonyldiimidazole in an aprotic solvent for about 8 to about 24 hours at temperatures of about xe2x88x9230xc2x0 C. to about 45xc2x0 C. to provide the compound of formula (IIIxe2x80x2) 
The reaction can require cooling or heating from about xe2x88x9220xc2x0 C. to about 45xc2x0 C., depending on the conditions used, and preferably from about 0xc2x0 C. to about 35xc2x0 C. The reaction requires from about 0.5 hours to about 10 days, and preferably from about 10 hours to about 2 days, to complete. Portions of this reaction sequence follow the procedure described by Baker et al., J. Org. Chem., 1988, 53, 2340. Compound (IIIxe2x80x2) is then converted into an 11,12-cyclic carbamate by reacting it with ammonia or ammonium hydroxide. A base, such as potassium t-butoxide, can be optionally added to faciliate the cyclization.
Alternatively, the 11,12-diol is treated with a methanesulfonyl derivative followed by treatment with an amine base to give a 1,2-dihydroxy enone intermediate of the formula: 
The preferred reagent for preparing compound (IIIxe2x80x3) is methanesulfonic anhydride in pyridine, followed by an amine base, such as DBU in acetone or benzene. Treatment of compound having the formula (IIIxe2x80x2) with 1,1xe2x80x2-carbonyldiimidazole gives a compound of formula (IIIxe2x80x2). Treatment of compound of formula (IIIxe2x80x2) with ammonia optionally in the presence of base converts the 12-acylimidazolide intermediate into an 11,12-cyclic carbamate.
The cladinose moiety of the macrolide can be removed by hydrolysis in the presence of a mild aqueous acid to provide 2. Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid. Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol and the like. Reaction times are typically 0.5 to 24 hours. The reaction temperature is preferably from about xe2x88x9210xc2x0 C. to about 60xc2x0 C.
The 3-hydroxyl group of 2 can be oxidized to the ketone (IV) using a modified Swern oxidation procedure or Corey-Kim oxidation conditions. In one method, a diacyl chloride, such as oxalyl chloride, promotes the activation of a suitable oxidizing agent, for example, dimethyl sulfoxide, to give the dimethyl alkoxysulfonium salt of 2. Treatment of the resulting intermediate with a secondary or tertiary amine base affords the corresponding ketone. The preferred bases for the reaction are diethylamine, triethylamine and Hunig""s base.
Other suitable oxidizing agents include, but are not limited to, N-chloro-succinimide-dimethyl sulfide, carbodiimide-dimethylsulfoxide, and the like. In a typical example, compound 2 is added into a pre-formed N-chlorosuccinimide and dimethyl sulfide complex in a chlorinated solvent such as methylene chloride at xe2x88x9210 to 25xc2x0 C. After being stirred for 0.5-4 hours, a tertiary amine, such as triethylamine or Hunig""s base, is added to produce the corresponding ketone.
Alternatively, a compound containing a ruthenium transition metal is suitable for carrying out the oxidation reaction in an organic solvent. An exemplary reagent is tetrapropyl-perruthenate (TPAP). The preferred solvent for the reaction is methylene chloride.
Deprotection of the 2xe2x80x2-hydroxyl group provides the desired ketolide (IV). When the protecting group is an ester such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When Rp is a trialkylsilyl group, the compound may be deprotected by treatment with a source of fluoride in THF or acetonitrile.
According to the alternate procedure shown in Scheme 3, the compound (Ixe2x80x2), which is the 9-oxime compound of erythromycin A, is subjected to acid hydrolysis with dilute mineral or organic acid as described previously to remove the cladinose moiety and give compound 3. The 3- and 2xe2x80x2-hydroxyl groups and the oxime can be appropriately protected with a suitable protecting reagent as previously described, to give the compound 4. The protection is accomplished either simultaneously for the oxime and the hydroxyl groups or in steps, by protecting and isolating each functional group individually with the previously described protecting reagents. Compound 4 is then allylated, deprotected and deoximated as described previously for Scheme 1 to give compound 5. The 2xe2x80x2-hydroxyl and 3-hydroxyl group of compound 5 are optionally protected and reacted with N,N-carbonyldiimidazole and sodium hexamethyldisilazide followed by reaction with ammonia and subsequent deprotection of 2xe2x80x2- and 3-hydroxyl groups to give the carbamate 2. Oxidation of compound 2 affords the compound of formula (IV). 
The present invention also relates to intermediate compounds represented by a compound of the formula: 
wherein Vxe2x80x2 is oxygen or Nxe2x80x94Oxe2x80x94R14; wherein R14 is selected from the group consisting of acetyl, benzoyl or trimethylsilyl; Rpxe2x80x2 is independently selected at each occurrence from acetyl, benzoyl or trimethylsilyl; L and T are each hydroxyl; or L taken together with T forms an 11,12-carbamate; and Ra as previously defined. Preferably, R14 and Rpxe2x80x2 are each acetyl or benzoyl.
In a preferred embodiment, Ra is 3-(3-quinolyl)-2-propenyl or 2-allyl, and Rpxe2x80x2 is benzoyl.
Abbreviations used in the examples are: Ac for acetyl; THF for tetrahydrofuran; CD1 for 1,1xe2x80x2-carbonyldimethylformamide; DBU for 1,8-diazabicyclo[5.4.0]-undec-7-ene; DMSO for dimethylsulfoxide; and TMSCl for trimethylsilyl chloride; dppb for 1,4-bis(diphenylphosphine)butane; Pd2(dba)3 for tris(dibenzylideneacetone)dipalladium; IPAC for isopropyl acetate; MTBE for methyl t-butyl ether; DMAP for N,N-dimethylamino-pyridine; and IPA for isopropyl alcohol.
Starting materials, reagents and solvents were purchased from Aldrich Chemical Company (Milwaukee, Wis.), unless otherwise noted below.
The compounds and processes of the invention will be better understood in connection with the Reference Examples and Example s, which are intended as an illustration of and not a limitation upon the scope of the invention as defined in the appended claims.
The following Reference Examples illustrate the preparation of suitable alkylating agents for the process of the invention. The alkylating agents provide a group represented by Ra, as previously described, which can be attached to the 6-O-position of an erythromycin or ketolide derivative. The Reference Examples, below, are not intended to describe the preparation of an exhaustive list of alkylating agents for the invention.
The starting materials and the amounts used are set forth in Table 1 below.
Methods of preparing the carbonates were carried out in accordance with procedures as described in Houlihan et al., Can. J. Chem. 1985, 153. A 3-L three-necked round-bottom flask equipped with mechanical stirring, a nitrogen inlet adapter and a pressure equalizing addition funnel was charged with allyl alcohol, di-t-butyl dicarbonate, and CH2Cl2 and cooled to 0xc2x0 C. A 0xc2x0 C. solution of 30% NaOH (aq.) was added dropwise to the rapidly stirring solution at such a rate that the internal temperature did not rise above 20xc2x0 C. (about 1 hour). The reaction mixture was stirred at 20xc2x0 C. for 2 hours prior to work-up.
The crude reaction mixture was partitioned between 1 L water and 500 mL CH2Cl2. The organic layer was separated, washed with 1 L water and 1 L saturated NaCl solution, dried over MgSO4, filtered and reduced to dryness in vacuo, to afford about 300 g of a yellow oil. The crude product was purified by fractional distillation, bp 96xc2x0 C. at 70 mmHg, affording the product as a colorless oil, 250.3 g (68%). 1H NMR (CDCl3, 300 MHz): xcex45.95 (m, 1H), 5.3 (appar quartet of quartets, 2H), 4.55 (appar doublet of triplets, 2H), 1.49 (s, 9H). 13C NMR (CDCl3, 75 MHz): xcex4153.1, 131.9, 118.3, 81.9, 67.4, 27.6. MS (NH3, Cl): 176 (M+NH4)+. Anal Calc""d for C8H14O3: C, 60.73; H, 8.92. Found: C, 60.95; H, 8.96.
Step (1): Preparation of 3-(3-quinolyl)-2-propyn-1-ol (compound (i))
To a dry 2-L three-necked flask previously purged with nitrogen, was charged 3-bromoquinoline (118.77 g, 570 mmol), propargyl alcohol (71.9 g, 1.28 mol, 2.25 equiv), triethylamine (1500 mL), copper(I) iodide (3.62 g, 19 mmol, 0.033 equiv) and dichlorobis(triphenylphosphine) palladium(II) (6.67 g, 9.5 mmol). The resulting mixture was mechanically stirred and heated to reflux for 3 hours. Upon cooling, the triethylamine solution was filtered and washed with triethylamine (300 mL). The filtrate was then concentrated under reduced pressure to provide solids which were suspended in 5% aq. NaHCO3 (600 mL) and extracted with ethyl acetate (1xc3x97600 mL). The solids which were left after filtration were treated in the same manner (i.e., suspend in aq. 5% NaHCO3 and extracted with ethyl acetate). The combined ethyl acetate extracts were stirred with silica gel (15 g) and decolorizing carbon (3 g) before being filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to provide a tan colored solid which was dried in the vacuum oven at 45xc2x0 C. overnight. The 3-(3-quinolyl)-2-propyn-1-ol was thus isolated. 92.14 g, 88.3% yield. MS(Cl): (M+H)+ at 184; NMR (300 MHz CDCl3) xcex4: 4.58 (s, 2H), 4.70 (s, broad, 1H), 7.57 (m,1H), 7.70 (m, 1H), 7.77 (d, 1H), 8.10 (d, 1H), 8.10 (s, H), 9.05 (s, 1H).
Step (2A): Preparation of cis-3-(3-quinolyl)-2-propen-1-ol (compound (ii))
To a 1-L three-necked round-bottom flask was charged 3-(3-quinolyl)-2-propyn-1-ol (31.65 g, 173 mmol), ethanol (550 mL) and 5% palladium on calcium carbonate poisoned with lead (Lindlar catalyst, 750 mg, 0.0024 equiv). The atmosphere above the heterogeneous mixture was purged with hydrogen after which time hydrogen was delivered to the reaction via a balloon. The progress of the reaction was monitored by TLC (1:1 ethyl acetate/heptane). Upon reaction completion (xcx9c16 hours), the mixture was purged with nitrogen and vacuum filtered through a bed of diatomaceous earth. The product filtrate was then concentrated under reduced pressure. The residue which resulted was dissolved in ethyl acetate (750 mL) and extracted with 2 N HCl (2xc3x97750 mL). The aqueous acidic product solution was then adjusted to pH 9 with 2 N NaOH and then back extracted with isopropyl acetate (2xc3x97700 mL). The organic layer was then dried over Na2SO4, filtered and concentrated to an oil under reduced pressure. The product oil 3-(3-quinolyl)-2-propen-1-ol (29.5 g, 92.2%) consisted of a mixture of both cis and trans alkenols and was subjected to flash chromatography (1:1 ethyl acetate/heptane) to isolate pure cis alkenol.
m.p. 81-82xc2x0 C. 1H NMR (300 MHz, CDCl3) xcex48.71 (d, J=2.2 Hz, 1H), 8.04 (dd, J=8.4, 0.9 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.74 (m, 1H), 7.66 (m, 1H), 7.51 (m, 1H), 66.1 (br d, J=11.8 Hz, 1H), 6.13 (dt, J=11.8, 6.5 Hz, 1H), 4.81 (dd, J=6.4, 1.7 Hz, 2H). 13C NMR (75 MHz, CDCl3) xcex4150.8, 146.5, 135.0, 134.4, 129.6, 129.5, 128.7, 127.8, 127.5, 126.9, 126.9, 59.0. Anal. Calc""d for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.89; H, 6.03; N, 7.49.
Step (2B): Preparation of 3-(3-quinolyl) trans-2-propen-1-ol
To a dry 250-mL three-necked jacketed round-bottom flask was charged sodium bis(2-methoxyethoxy)aluminum hydride. (Red-Al, 70% wt. solution in toluene, 11.0 g, 38.1 mmol, 1.39 equiv) and anhydrous THF (20 mL). To this precooled (0-2xc2x0 C.) and magnetically stirred solution was added a THF (50 mL) solution of the 3-(3-quinolyl)-2-propyn-1-ol (5.0 g, 27.32 mmol) via a pressure equalizing dropping funnel. The temperature was not allowed to rise above 15xc2x0 C. After the addition was complete (20 minutes) the mixture was allowed to warm up to room temperature and stirred for one hour. The solution was then cooled back to 0xc2x0 C. and quenched by the addition of aqueous 10% sulfuric acid (20 mL) such that the internal temperature did not rise above 15xc2x0 C. The biphasic reaction mixture was then basified to pH 9-10 with aq. conc. NH4OH and the aqueous layer was back extracted with ethyl acetate (2xc3x97125 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give exclusively 3-(3-quinolyl) trans-2-propen-1-ol as a solid: 4.1 g, 81%.
1H NMR (300 MHz, DMSO-xcex46): 9.17 (d, J=2.5 Hz, 1H), 8.39 (d, J=2.5 Hz, 1H), 8.10-8.0 (m, 2H), 7.82-7.64 (m, 2H), 6.90-6.75 (m, 2H), 5.15 (t, J=5.6 Hz, 1H), 4.30 (dd, J=5.6, 3.0 Hz, 2H), 3.51 (s, 1H). 13C NMR (75 MHz, DMSO-xcex46): d 149.3, 146.7, 133.6, 131.8, 130.0, 129.0, 128.7, 128.0, 127.4, 126.9, 125.0, 61.5. Anal. Calc""d for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.75; H, 5.83; N, 7.50.
Step (3): Preparation of 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate
To a 500-mL three-necked round-bottom flask equipped with an overhead mechanical stirrer was charged 3-(3-quinolyl)-2-propen-1-ol (13.03 g, 70.43 mmol) as a mixture of cis and trans isomers (81% cis, and 19% trans), di-t-butyl dicarbonate (16.91 g, 77.48 mmol, 1.11 equiv), tetra n-butyl ammonium hydrogensulfate (742 mg, 2.17 mmol) and methylene chloride (135 mL). The stirred mixture was cooled to 0 to 5xc2x0 C. at which time aqueous 25% sodium hydroxide (33.3 mL) was added over 45 minutes such that the internal temperature did not rise above 20xc2x0 C. Upon completion of the reaction (1 to 4 hours), the reaction mixture was diluted with methylene chloride (50 mL) and washed with water (2xc3x97125 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate: 18.35 g (91.4%) as an oil. This material can be further purified by chromatography on silica gel to provide purified carbonate as a colorless oil which retains the original ratio of cis and trans isomers: 17.50 g, 87.2%.
For cis isomer: m.p. 57-58xc2x0 C. 1H NMR (300 MHz, CDCl3) xcex48.78 (d, J=2.2 Hz, 1H), 8.07 (m, apparent d, J=8.5 Hz, 1H), 7.93 (d, J=2.0 Hz, 11H), 7.78 (dd, J=8.1, 1.0 Hz, 1H), 7.68 (m, 1H), 7.52 (m, 1H), 6.76 (br d, J=11.7 Hz, 1H), 6.05 (dt, J=11.8, 6.6 Hz, 1H), 4.88 (dd, J=6.6, 1.7 Hz, 2H), 1.47 (s, 9H). 13C NMR (75 MHz, CDCl3) xcex4153.1, 150.8, 147.0, 134.7, 129.5, 129.3, 129.1, 128.8, 127.8, 127.4, 126.9, 82.4, 63.3, 27.6. Anal. Calc""d for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.31; H, 6.62; N, 4.91.
For trans isomer: m.p. 55-56xc2x0 C. 1H NMR (300 MHz, CDCl3): xcex49.00 (d, 1H), 8.08 (br dd, 1H), 7.80 (dd, 1H), 7.72-7.65 (m, 1H), 7.58-7.51 (m, 1H), 6.83 (br d, J=16.2 Hz, 1H), 6.52 (dt, J=16.2, 5.9 Hz, 1H), 4.80 (dd, J=5.9, 1.1 Hz, 1H), 1.52 (s, 9H). 13C NMR (75 MHz, CDCl3): xcex4153.2, 149.1, 147.6, 132.9, 130.6, 129.4, 129.2, 129.0, 127.8, 126.9, 125.4, 82.4, 67.0, 27.7. Anal. Calc""d for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.59; H, 6.81; N, 4.80.
Step (1): Preparation of Cis-3-(3-quinolyl)-2-propen-1-ol
To a dry 3000-mL three-necked jacketed flask, equipped with a thermocouple was charged 3-(3-quinolyl)-2-propyn-1-ol (76 g, 415.3 mmol), 5% Pd/CaCO3 (1.52 g) and 3,6-dithia-1,8-octanediol (0.76 g). 3A Ethanol (1125 mL) was then charged and the mixture which resulted was vigorously stirred at ambient temperature (19xc2x0 C.). The atmosphere above the mixture was purged with hydrogen and then evacuated. This purging and evacuating process was repeated twice. Hydrogen balloons (0.32 psi) were placed above the reaction mixture and the progress of the reduction was monitored by HPLC analysis. After 25 hours, the reaction was stopped.
The mixture was filtered through a bed of diatomaceous earth and the flask and cake were washed with 3A ethanol. The filtrate was concentrated under reduced pressure. The residue was dissolved in methyl isobutyl ketone (MIBK, 400 mL) and this solution was passed through a plug of filter aid (38 g). MIBK (125 mL) was used to rinse the flask and cake until the filtrate was colorless. The combined filtrates were concentrated to a volume of 200 mL then diluted with MIBK (270 mL) at which time the crystallization of the cis-3-(3-quinolyl)-2-propen-1-ol initiated. The crystallizing solution was then slowly triturated with heptane (270 mL) with stirring and later cooled at 0xc2x0 C. overnight. The product was washed with cold MIBK/heptane (3:4, 150 mL). The wet cake was dried in a vacuum oven at 50xc2x0 C. for 6 hours to give cis-3-(3-quinolyl)-2-propen-1-ol (50.0 g, 70.0% yield, adjusted for potency of starting material). Purity as determined by HPLC was 98.9%.
Step (2): Boc Protection of Cis-3-(3-quinolyl)-2-propen-1-ol
The solid cis-3-(3-quinolyl)-2-propen-1-ol (10.0 g, 54.1 mmol), di-t-butyl dicarbonate (17.6 g, 80.6 mmol, 1.5 equiv), toluene (43 g) and tetra-n-butylammonium hydrogensulfate (0.68 g, 2.0 mmol) were combined and stirred (mechanically) in a three-necked round-bottom flask. To this stirring mixture was slowly added an aqueous sodium hydroxide solution (28 g H2O and 7.0 g, NaOH) over 10 minutes. The temperature of the biphasic mixture warmed from 18xc2x0 C. to 31xc2x0 C. over 1.5 hours and was allowed to stir overnight at room temperature. The reaction was then diluted with toluene (33 mL) and water (19 mL). The layers were separated (aq. pH 12) and the organic was washed consecutively with water (1xc3x9728 mL) and 5% aq. NaCl (1xc3x9728 mL). The organic layer was then washed with an aqueous sodium chloride solution (7 g NaCl, 28 g H2O) before concentration under reduced pressure and a bath temperature of 50xc2x0 C. The oil which resulted was dissolved in heptane (100 g) and concentrated by rotary evaporation (2xc3x97). The resulting residue was dissolved in 55 mL of heptane for crystallization. The product was collected at xe2x88x925xc2x0 C., washed with cold heptane (10 mL) and vacuum dried at room temperature to provide a white to off-white colored solid (13.6 g, 88.3%). Purity as determined by HPLC was 98.7%.
Isopropyl alcohol (2-propanol, 31.0 mL, 24.3 g, 0.4 mol, 1.1 equiv), pyridine (64.0 mL, 62.6 g, 0.79 mol, 2.1 equiv), and 500 mL methyl tertiary butyl ether (MTBE) were charged to a suitable reaction vessel and cooled to 0xc2x0 C. A solution of allyl chloroformate (40.0 mL, 45.4 g, 0.38 mol, 1.0 equiv) in 100 mL of MTBE was added over the course of 10 minutes. The reaction mixture was allowed to stir at 0xc2x0 C. for 30 minutes prior to warming to room temperature (xcx9c25xc2x0 C.) and stirring overnight (xcx9c16 hours). The crude reaction mixture was then filtered through a 1-inch plug of diatomaceous earth (which was then washed with 200 mL of MTBE) and the combined organic layers were washed twice with 200 mL of 20% conc. HCl solution, three times with 200 mL of distilled water, dried over MgSO4 and reduced to dryness in vacuo affording 37.4 g (69%) of the crude carbonate as a colorless oil. The crude oil from this experiment was combined with that from an earlier experiment and they were purified together as a single lot by vacuum distillation (b.p. 74-76xc2x0 C. at 48-53 mmHg pressure). All spectral data is consistent with the proposed structure.
1H NMR (300 MHz, CDCl3) xcex4: 5.95 (m, 1H), 5.30 (m, 2H), 4.89 (appar septet, 1H), 4.61 (m, 2H), 1.3 (d, 6H); 13C NMR (75 MHz, CDCl3) xcex4: 154.2, 131.6, 118.1, 71.5, 67.7, 21.4, MS (DCI-NH3): 145 (M+H)+
To a stirred solution of quinoline-3-carboxaldehyde (3 g, 19.1 mmol) in tetrahydrofuran (15 mL) at xe2x88x9210xc2x0 C., was added vinyl magnesium chloride solution in THF (11.3 mL, 15 wt. %, d=0.975) at xe2x88x925 to xe2x88x9210xc2x0 C. At the end of the addition, HPLC showed the reaction was complete. This brown solution was transferred by cannula to a stirred solution of di-t-butyl dicarbonate (4.4 g, 22.9 mmol) in THF (10 mL) at xe2x88x9210 to xe2x88x9215xc2x0 C. After the transfer, the reaction mixture was warmed to 0-5xc2x0 C. for 1 hour. The mixture was cooled back down to xe2x88x9210xc2x0 C., diluted with 60 mL of methyl t-butyl ether and quenched with a solution of citric acid (4.8 g, 22.9 mmol) in water (27 mL) at  less than 5xc2x0 C. After 5 hours of mixing, the organic layer was separated, washed with 30 mL of 7% sodium bicarbonate, 2xc3x9730 mL water, and filtered. The filtrate was concentrated under vacuum to give a light brown oil (5.5 g). Column chromatography (silica gel, 20:80 EtOAc/hexane) of the crude product gave pure carbonate (4.3 g). Yield was 79.0%.
1H NMR (300 MHz, CDCl3) xcex4: 8.93 (appar d, 1H), 8.15 (m, 2H), 7.84 (appar dd, 1H), 7.76 (appar dt, 1H), 7.58 (appar dt, 1H), 6.35 (m, 1H), 6.15 (m, 1H), 5.4 (m, 2H), 1.48(s,9H). 13CNMR (75.5 MHz, CDCl3) xcex4: 149.8, 147.9, 135.3, 134.3, 131.5, 129.8, 129.3, 128.0, 127.6, 127.0, 90.4, 82.9, 77.1, 27.8. MS (DCI, NH3): 286 (M+H+). Anal Calc""d for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found C, 71.32; H, 6.75; N, 4.82.
Di-isopropyl amine (39.6 mL, 3 equiv) and 200 mL methyl tertiary butyl ether (MTBE) were charged to a suitable reaction vessel and cooled to 0xc2x0 C. A solution of allyl chloroformate (40.0 mL, 45.4 g, 0.38 mol, 1.0 equiv) in 100 mL of MTBE was added over the course of 60 minutes. The reaction mixture became very thick and an additional 200 mL of MTBE was added. The reaction mixture was warmed to room temperature and mixed for an additional 12 hours at which time it was filtered through a 1-inch plug of diatomaceous earth and washed twice with 100 mL of 0.1 N HCl, once with 100 mL of distilled water, dried over MgSO4, and reduced to afford 14.37 g of a colorless oil (83%) ( greater than 97% pure by GC). Material was pure enough to use without further purification, spectral data is consistent with this structure.
1H NMR (400 MHz, d5-pyridine) xcex46.02 (m, 1H), 5.30 (dq, 1H), 5.15 (dq, 1H), 4.72 (m, 2H), 3.95 (br s, 2H), 1.18 (d, 12H). 13C NMR (100 MHz, d5-pyridine) xcex4: 155.0, 134.3, 116.7, 65.1, 45.8 (br), 20.6 (br) MS (DCI-NH3): 186 (M+H)+.